PDF: RE-LY
(2009)Objective
To compare dabigatran (110 mg or 150 mg BID) with warfarin for stroke prevention in atrial fibrillation.
Study Summary
• Dabigatran 150 mg was superior to warfarin for stroke/systemic embolism prevention in non-valvular AF; • Dabigatran 110 mg was noninferior to warfarin with less major bleeding.
Intervention
Fixed-dose dabigatran (110 or 150 mg BID) vs. adjusted-dose warfarin (INR 2–3). Median follow-up: 2 years.
Inclusion Criteria
AF with at least one stroke risk factor (prior stroke/TIA, LVEF <40%, symptomatic CHF, age ≥75, or 65–74 with vascular risk factors).
Study Design
Arms: Dabigatran 110 mg BID vs. Dabigatran 150 mg BID vs. Warfarin
Patients per Arm: 110 mg: ~6015, 150 mg: ~6076, Warfarin: ~6022
Outcome
• Primary outcome: stroke/systemic embolism: 1.11%/yr (150 mg) vs. 1.69%/yr (warfarin). <br>• Major bleeding: lower with 110 mg; similar with 150 mg. <br>• Hemorrhagic stroke lowest with dabigatran..
Bottom Line
In patients with atrial fibrillation, dabigatran 150 mg twice daily was superior to warfarin for the prevention of stroke or systemic embolism, with similar rates of major bleeding but lower rates of life-threatening and intracranial bleeding. The 110 mg dose was noninferior to warfarin for stroke prevention and was associated with significantly lower rates of major bleeding.
Major Points
- First major DOAC trial — RE-LY launched the era of direct oral anticoagulants by demonstrating that dabigatran (a direct thrombin inhibitor) could match or beat warfarin for AF stroke prevention.
- 18,113 patients across 951 centers in 44 countries. Unique three-arm design: two blinded dabigatran doses (110 mg and 150 mg BID) vs open-label warfarin (PROBE design for warfarin comparison).
- Dabigatran 150 mg BID was SUPERIOR to warfarin: stroke/systemic embolism 1.11% vs 1.69%/yr (RR 0.66, 95% CI 0.53–0.82, p<0.001 for superiority). The only DOAC to demonstrate superiority over warfarin for stroke prevention.
- Dabigatran 110 mg BID was NONINFERIOR to warfarin: 1.53% vs 1.69%/yr (RR 0.91, p<0.001 for noninferiority). This dose was approved outside the US but not in the US (FDA approved only 150 mg and 75 mg).
- Both doses dramatically reduced hemorrhagic stroke vs warfarin: 150 mg: 0.10% vs 0.38%/yr (RR 0.26, p<0.001); 110 mg: 0.12% vs 0.38%/yr (RR 0.31, p<0.001). This was the most consistent benefit across all DOACs vs warfarin.
- Major bleeding: 150 mg was similar to warfarin (3.11% vs 3.36%/yr, p=0.31); 110 mg was significantly lower (2.71%/yr, p=0.003). GI bleeding was higher with 150 mg (1.51% vs 1.02%/yr, p<0.001).
- MI signal: both dabigatran doses showed numerically higher MI rates (150 mg: 0.74% vs 0.53%/yr, RR 1.38, p=0.048) — a controversial finding possibly explained by warfarin's anti-thrombotic properties on coronary plaque.
- Dyspepsia was significantly more common with dabigatran (11.3% vs 5.8%) — the tartaric acid coating required for absorption was the cause, and it was a major driver of drug discontinuation.
- Idarucizumab (Praxbind) was subsequently developed as a specific reversal agent for dabigatran — the first DOAC reversal agent approved.
- Led to FDA approval of dabigatran in 2010, making it the first DOAC available in the US. Launched a paradigm shift from warfarin to DOACs for AF, followed by ROCKET AF (rivaroxaban), ARISTOTLE (apixaban), and ENGAGE AF-TIMI 48 (edoxaban).
Study Design
- Study Type
- Randomized, noninferiority trial.
- Randomization
- Yes
- Blinding
- Dabigatran doses were administered in a blinded fashion; warfarin was administered in an open-label fashion. Outcomes were adjudicated by a blinded committee.
- Sample Size
- 18113
- Follow-up
- Median of 2.0 years.
- Centers
- 951
- Countries
- 44 countries
Primary Outcome
Definition: The primary outcome was stroke or systemic embolism.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1.69% per year | 1.11% per year (for 150 mg dose) | 0.66 (0.53 to 0.82) | <0.001 for superiority |
Limitations & Criticisms
- PROBE design with open-label warfarin — the most criticized aspect of the trial. Knowledge of treatment assignment could influence anticoagulation management and event reporting, despite blinded adjudication.
- MI signal with both dabigatran doses (150 mg: RR 1.38, p=0.048) was concerning and unexpected — meta-analyses later suggested a ~30% increased MI risk, potentially limiting use in patients with coronary disease.
- GI bleeding was higher with 150 mg (1.51% vs 1.02%/yr, p<0.001) — particularly in elderly patients, making dose selection complex.
- Dyspepsia rate of 11.3% with dabigatran (vs 5.8% warfarin) — the tartaric acid formulation caused significant GI side effects and drug discontinuation in real-world use.
- Warfarin TTR of 64% was moderate — in centers with high TTR (>72%), warfarin was comparably effective, raising questions about whether the trial demonstrated dabigatran superiority or warfarin inferiority.
- No dose reduction criteria were built into the trial — the FDA later approved 75 mg for CrCl 15–30 mL/min based on PK modeling alone, not RE-LY data.
- Industry-sponsored (Boehringer Ingelheim) — and there were later controversies about bleeding event reporting and FDA inspection findings.
- Drug interactions not well characterized — dabigatran is a P-glycoprotein substrate, and concurrent P-gp inhibitors (amiodarone, dronedarone, verapamil) increase levels significantly.
- No head-to-head comparison with other DOACs — clinical decision-making between dabigatran, rivaroxaban, apixaban, and edoxaban relies on indirect comparisons.
Citation
N Engl J Med 2009;361:1139-51.